Relationship of Apo B and BHMT: Nutrition and Physiology

Apo B 和 BHMT 的关系：营养和生理学

• 批准号: 6434461
• 负责人: JANET DEHOFF SPARKS
• 金额: $ 19.69万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6434461
• 关键词: apolipoprotein B; betaine compound; cell line; diet; gene environment interaction; gene expression; gene targeting; genetically modified animals; homocysteine; immunoprecipitation; laboratory mouse; laboratory rabbit; laboratory rat; liver cells; liver metabolism; messenger RNA; methylation; methyltransferase; nutrition related tag; protein metabolism; protein protein interaction; radioassay; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Apolipoprotein B (Apo B) is important in lipid transport in lipoproteins (LP), and as a factor associated with risk of macrovascular disease complications (heart attacks, strokes). B48 and B100 are forms of apo B that, in humans, represent intestinal and hepatic products of translation that are derived from edited and unedited apo B mRNA transcribed from a single copy gene. In McArdle RH-7777 (McA) cells, the restoration of betaine homocysteine S-methyltransferase (BHMT) expression through transfection is positively correlated with apo B mRNA abundance and increases in B48 and B100 secretion. BHMT catalyzes transfer of a methyl group from betaine to homocysteine to form methionine. BHMT and methionine synthase contribute equally to methionine formation from homocysteine in rat liver. BHMT can be induced in a variety of nutritional states in vivo. Aim 1 is to establish the physiological relationship between BHMT and apo B. Using dietary conditions that alter BHMT expression, changes in apo B mRNA will be evaluated in rats. Aim 2 will evaluate the impact of apo B mRNA and BHMT pathways on hepatic lipoprotein metabolism in rat hepatocytes (RH) and BHMT-transfected McA cells. Hepatic biogenesis of B100 and B48 will be studied including apo B translation, intracellular LP assembly, apo B degradation, and LP secretion. In order to assess mechanisms of apo B mRNA abundance changes, apo B mRNA stability and apo B gene transcription will be documented. BHMT may function in hepatic lipid metabolism directly, and experiments will test whether BHMT mediates methyl transfer from betaine to phosphatidylethanolamine in the formation of phosphatidyicholme necessary in apo B-Lp secretion. The overall research goal is to understand and characterize BHMT metabolic pathways and potential relationships to apo B biogenesis. A potential link of two pathways whose products or intermediates are associated with increased cardiovascular disease risk could be established.

描述（由申请人提供）：载脂蛋白B（APO B）在脂蛋白（LP）中的脂质转运中很重要，并且是与大型疾病并发症风险（心脏病发作，中风）有关的因素。 B48和B100是Apo B的形式，在人类中，它代表了翻译的肠和肝产物，这些肠道和肝产品是从单个副本基因转录的编辑和未经编辑的Apo B mRNA中得出的。 在McArdle RH-7777（MCA）细胞中，通过转染的Betaine同型半胱氨酸S-甲基转移酶（BHMT）表达的恢复与APO B mRNA的丰度正相关，而B48和B100分泌中的增加和增加。 BHMT催化甲基从甜菜碱到同型半胱氨酸的转移以形成蛋氨酸。 BHMT和蛋氨酸合酶有助于 大鼠肝脏中同型半胱氨酸的蛋氨酸形成同样。可以在体内在各种营养状态下诱导BHMT。 目的1是建立BHMT和ApoB之间的生理关系。使用改变BHMT表达的饮食条件，将评估Apo B mRNA的变化。 AIM 2将评估APO B mRNA和BHMT途径对大鼠肝细胞（RH）和BHMT转染的MCA细胞中肝脂蛋白代谢的影响。将研究B100和B48的肝生物发生，包括APO B翻译，细胞内LP组件，APO B降解和LP分泌。为了评估APO B mRNA丰度变化的机制，将记录APO B mRNA稳定性和APO B基因转录。 BHMT可能直接在肝脂质代谢中发挥作用，实验将测试BHMT是否介导了从Betaine到磷脂酰乙醇胺的甲基转移，以形成Apo B-LP分泌所必需的磷脂酰基乙醇。 总体研究目标是了解和表征BHMT代谢途径和与Apo B生物发生的潜在关系。可以建立两个途径的潜在联系，其产品或中间体与心血管疾病风险增加有关。